Response to chemotherapy could predict the prognosis of esophageal squamous cell carcinoma treated with neoadjuvant docetaxel, cisplatin, and fluorouracil (DCF) followed by surgery: long-term results in a single institute.

BACKGROUND: Preoperative chemotherapy with 5-fluorouracil and cisplatin (FP) followed by surgery has been considered a standard treatment for patients with stage II/III esophageal squamous cell carcinoma (ESCC) based on the results of a phase III trial (JCOG9907) in Japan. Subsequently, the phase III NExT trial (JCOG1109) revealed the survival benefit of the neoadjuvant DCF regimen, which adds docetaxel to FP, and it became a standard treatment. However, the long-term results and prognostic factors of neoadjuvant DCF therapy in the real world are unknown. METHODS: We retrospectively investigated 50 patients with ESCC treated with neoadjuvant DCF therapy from July 2012 to December 2017 at The University of Tokyo Hospital. RESULTS: Median overall survival (OS) and progression-free survival (PFS) were 32.3 [95% confidence interval (CI) 21.0-NA] and 10.0 months (95% CI 6.3-15.6), respectively. Median OS [not reached (95% CI 31.5-NA) vs. 21.4 months (95% CI 13.5-33.0); p = 0.028] and PFS [83.3 months (95% CI 6.4-NA) vs. 7.4 months (95% CI 6.0-12.8] were significantly longer in patients with an objective response than in non-responders. Of 44 surgical cases, median PFS tended to be longer in pathological lymph node metastasis-negative patients. Conversely, survival did not differ according to cStage (II/III vs. IV) or the average relative dose intensity (ARDI, ≥ 85% vs. < 85%). DISCUSSION: The response to neoadjuvant DCF therapy could predict patient prognosis. Additionally, pN+ tended to increase the recurrence risk, whereas cStage and ARDI did not influence survival.

First case report of intestinal lymphangiectasia with refractory bleeding from the duodenum, successfully treated by intra-abdominal lymphaticovenous anastomosis with venous ligation.

Intestinal lymphangiectasia (IL) is a protein-losing enteropathy (PLE) that occasionally leads to gastrointestinal bleeding (GIB). We encountered a 41-year-old female with a 9-year history of duodenal IL with PLE and GIB that progressively worsened. Despite a diet, supplemented with medium-chain triglycerides, antiplasmin therapy, oral corticosteroids, octreotides, sirolimus, and repeated endoscopic hemostasis, her symptoms remained uncontrolled, leading to blood transfusion dependence. Lymphangiography revealed significant leakage from abnormal abdominal lymph vessels into the duodenal lumen. The patient subsequently underwent an abdominal-level lymphaticovenous anastomosis combined with local venous ligation. This approach resulted in a dramatic improvement and sustained resolution of both the PLE and GIB. More than 6 months after surgery, the patient remained free of symptoms and blood transfusion dependence.

Preoperative NUn score serves as a robust predictor of overall and disease-specific survivals following radical surgery for gastric cancer.

PURPOSE: Methods to preoperatively stratify oncological risks associated with gastric cancer (GC) are limited. Host inflammatory parameters, i.e., serum C-reactive protein (CRP) and albumin levels, are known to be associated with outcomes. We examined the relationships between disease-specific mortality and four CRP-albumin-based indices (CRP-albumin ratio [CAR], modified Glasgow prognostic score [mGPS], Osaka prognostic score [OPS], and NUn score) preoperatively measured in cases with resectable GC. METHODS: Survival outcomes of 1290 consecutive GC patients with oncological gastrectomy were reviewed. Predictive significances of preoperative CAR, mGPS, OPS, and NUn scores were assessed with time-dependent receiver operating characteristic curves and Cox regression analyses. RESULTS: Median follow-up was 107 months. Area under the curve for predicting overall and disease-specific survivals (OS/DSS) for the preoperative NUn score was clearly superior to those of the other parameters. On univariate Cox regression analysis, preoperative CAR, mGPS, OPS, and the NUn score all correlated significantly with OS/DSS. On multivariate Cox regression analysis, the preoperative NUn score, as a continuous variable, showed an independent relationship with OS (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.16-1.50, per 1-unit increase, P < 0.001) and even DSS (HR 1.23, 95% CI 1.02-1.49, P = 0.032). The other three markers failed to maintain independence for DSS. CONCLUSIONS: Preoperative NUn scores are stably associated with outcomes, including disease-specific mortality, possibly serving as a simple measure to define the likelihood of progression to systemic disease after meticulous surgery for GC, which may contribute to identifying patients who would benefit from additional modalities.

Percent vital capacity predicts postoperative sarcopenia after esophagectomy in initially nonsarcopenic esophageal cancer patients: a retrospective cohort study.

PURPOSE: The development of sarcopenia after esophagectomy is reported to affect the outcomes of patients with esophageal cancer (EC); however, the characteristics of patients likely to be predisposed to postoperative sarcopenia have not been defined. This study explores the associations between preoperative respiratory function and surgery-induced sarcopenia in EC patients confirmed as nonsarcopenic preoperatively. METHODS: The subjects of this retrospective review were 128 nonsarcopenic patients who underwent esophagectomy for EC. We took body composition measurements and performed physical function tests 3 and 6 months postoperatively, to establish whether sarcopenia was present, according to the 2019 Asian Working Group for Sarcopenia guideline. We defined patients with surgery-induced sarcopenia as those with evidence of the development of sarcopenia within 6 months postoperatively or those with documented sarcopenia at 3 months but who could not be evaluated at 6 months. RESULTS: Surgery-induced sarcopenia developed in 19 of the 128 patients (14.8%), which correlated significantly with the preoperative %VC value (p < 0.01), but not with the preoperative FEV1.0% value. We set the lower quartile %VC value (91%) as the cut-off for predicting surgery-induced sarcopenia. A low %VC was independently associated with surgery-induced sarcopenia (odds ratio: 5.74; 95% confidence interval: 1.99-16.57; p < 0.01). CONCLUSIONS: Based on the findings of this study, %VC was a simple but valuable factor for predicting sarcopenia induced by esophagectomy.

Lymphatic flow mapping using near-infrared fluorescence imaging with indocyanine green helps to predict lymph node metastasis intraoperatively in patients with esophageal or esophagogastric junction cancer not treated with neoadjuvant chemotherapy.

BACKGROUND: Lymphatic flow mapping using near-infrared fluorescence (NIR) imaging with indocyanine green (ICG) has been used for the intraoperative prediction of lymph node metastasis in esophageal or esophagogastric junction cancer. However, a consistent method that yields sufficient diagnostic quality is yet to be confirmed. This study explored the diagnostic utility of our newly established lymphatic flow mapping protocol for predicting lymph node metastasis in patients with esophageal or esophagogastric junction cancer. METHODS: We injected 0.5 mL of ICG (500 µg/mL) into the submucosal layer at four peritumoral points on the day before surgery for 54 patients. We performed lymphatic flow mapping intraoperatively using NIR imaging. After determining the NIR status and presence of metastases, evaluable lymph node stations on in vivo imaging and all resected lymph nodes were divided into four categories: ICG+meta+ (true positive), ICG+meta- (false positive), ICG-meta+ (false negative), and ICG-meta- (true negative). RESULTS: The distribution of ICG+ and meta+ lymph node stations differed according to the primary tumor site. Sensitivity and specificity for predicting meta+ lymph nodes among ICG+ ones were 50% (95% CI 41-59%) and 75% (73-76%), respectively. Predicting meta+ lymph node stations among ICG+ stations improved these values to 66% (54-77%) and 77% (74-79%), respectively. Undergoing neoadjuvant chemotherapy was an independent risk factor for having meta+ lymph nodes with false-negative diagnoses (odds ratio 4.82; 95% CI 1.28-18.19). The sensitivity of our technique for predicting meta+ lymph nodes and meta+ lymph node stations in patients who did not undergo neoadjuvant chemotherapy was 79% (63-90%) and 83% (61-94%), respectively. CONCLUSION: Our protocol potentially helps to predict lymph node metastasis intraoperatively in patients with esophageal or esophagogastric junction cancer undergoing esophagectomy who did not undergo neoadjuvant chemotherapy.

Effects of the preoperative use and dosage of steroids on postoperative complications of gastric cancer surgery.

PURPOSE: To investigate the effects of preoperative steroid administration, including dosage, on complications after gastrectomy for gastric cancer. METHODS: We reviewed patients who underwent gastrectomy for gastric and esophagogastric junctional adenocarcinoma between 2013 and 2019 at the Department of Gastrointestinal Surgery, The University of Tokyo. RESULTS: Among the total 764 patients eligible for inclusion in the study, 17 were on steroid medication preoperatively (SD group) and 747 were not (ND group). The hemoglobin, serum albumin levels, and respiratory functions were significantly lower in the SD group than in the ND group. The incidence of postoperative complications classified as Clavien-Dindo (C-D) ≥ 2 was significantly greater in the SD group than in the ND group (64.7% vs. 25.6%, p < 0.001). Intra-abdominal infection (35.2% vs. 9.6%, p < 0.001) and anastomotic leakage (11.8% vs. 2.1%, p < 0.001) occurred more frequently in the SD group than in the ND group. On multiple logistic regression analysis for C-D ≥ 3 postoperative complications, the odds ratio for oral steroid use ≥ 5 mg per day as prednisolone had the highest value, of 13.0 (95% confidence interval 2.46-76.2, p < 0.01). CONCLUSION: Preoperative oral steroid use was identified as an independent risk factor for postoperative complications after gastrectomy for gastric cancer. Furthermore, the complication rate appears to increase as the oral steroid dosage is increased.

Optimal criteria for predicting lymph node metastasis in esophageal squamous cell carcinoma by anatomical location using preoperative computed tomography: a retrospective cohort study.

PURPOSE: Predicting lymph node metastasis (LNM) in esophageal squamous cell carcinoma (ESCC) is critical for selecting appropriate treatments despite the low accuracy of computed tomography (CT) for detecting LNM. Variation in potential nodal sizes among locations or patients' clinicopathological background factors may impact the diagnostic quality. This study explored the optimal criteria and diagnostic ability of CT by location. METHODS: We retrospectively reviewed preoperative CT scans of 229 patients undergoing curative esophagectomy. We classified nodal stations into six groups: Cervical (C), Right-upper mediastinal (UR), Left-upper mediastinal (UL), Middle mediastinal (M), Lower mediastinal (L), and Abdominal (A). We then measured the short-axial diameter (SAD) of the largest lymph node in each area. We used receiver operating characteristics analyses to evaluate the CT diagnostic ability and determined the cut-off values for the SAD in all groups. RESULTS: Optimal cut-offs were 6.5 mm (M), 6 mm (C, L, and A), and 5 mm (UR and UL). Diagnostic abilities differed among locations, and UR had the highest sensitivity. A multivariate analysis showed poor differentiation to be an independent risk factor for a false-negative diagnosis (p = 0.044). CONCLUSIONS: Optimal criteria and diagnostic abilities for predicting LNM in ESCC varied among locations, and poor differentiation might contribute to failure to detect LNM.

Lymphatic invasion is a prognostic factor of pathological N0 esophageal squamous cell carcinoma.

Adjuvant treatment after upfront esophagectomy for esophageal squamous cell carcinoma (ESCC) is indicated only for patients with lymph node metastasis in Japan. However, the recurrence rate after curative resection is high even for node-negative patients; thus, understanding the prognostic factors for patients with node-negative ESCC, which still remains unidentified, is important. Here, we aimed to reveal the prognostic factors for the long-term outcomes of patients with node-negative ESCC. Moreover, we compared the long-term outcomes among high-risk node-negative and node-positive patients. This single-institution retrospective study included 103 patients with pT1b-3N0 ESCC who underwent upfront surgery to identify the population at a high risk of recurrence. To compare overall survival (OS) and recurrence-free survival (RFS) between high-risk node-negative and node-positive patients, 51 node-positive ESCC patients with pStage IIIA or less who had undergone upfront surgery were also included. Univariable and multivariable analyses were performed using the Cox proportional hazard regression model. OS and RFS were compared using the log-rank test. Only lymphatic invasion (Ly+) was associated with worse 3-year OS (hazard ratio, 8.63; 95% confidence interval, 2.09-35.69; P = 0.0029) and RFS (hazard ratio, 4.87; 95% confidence interval, 1.69-14.02; P = 0.0034). The node-negative and Ly+ patients showed significantly worse OS (P = 0.0242) and RFS (P = 0.0114) than the node-positive patients who underwent chemotherapy. Ly+ is the only independent prognostic factor in patients with node-negative ESCC. Patients with node-negative and Ly+ ESCC may benefit from adjuvant treatment.

Efficacy and safety of a third-generation oncolytic herpes virus G47Δ in models of human esophageal carcinoma.

Treatment options are limited for esophageal carcinoma (EC). G47Δ, a triple-mutated, conditionally replicating herpes simplex virus type 1 (HSV-1), exhibits enhanced killing of tumor cells with high safety features. Here, we studied the efficacy of G47Δ using preclinical models of human EC. In vitro, G47Δ showed efficient cytopathic effects and replication capabilities in all eight human esophageal cancer cell lines tested. In athymic mice harboring subcutaneous tumors of human EC (KYSE180, TE8, and OE19), two intratumoral injections with G47Δ significantly inhibited the tumor growth. To mimic the clinical treatment situations, we established an orthotopic EC model using luciferase-expressing TE8 cells (TE8-luc). An intratumoral injection with G47Δ markedly inhibited the growth of orthotopic TE8-luc tumors in athymic mice. Furthermore, we evaluated the safety of applying G47Δ to the esophagus in mice. A/J mice inoculated intraesophageally or administered orally with G47Δ (107 plaque-forming units [pfu]) survived for more than 2 months without remarkable symptoms, whereas the majority with wild-type HSV-1 (106 pfu) deteriorated within 10 days. PCR analyses showed that the G47Δ DNA was confined to the esophagus after intraesophageal inoculation and was not detected in major organs after oral administration. Our results provide a rationale for the clinical use of G47Δ for treating EC.

Efficacy of a Third-Generation Oncolytic Herpes Virus G47Δ in Advanced Stage Models of Human Gastric Cancer.

Advanced gastric cancer, especially scirrhous gastric cancer with peritoneal dissemination, remains refractory to conventional therapies. G47Δ, a third-generation oncolytic herpes simplex virus type 1, is an attractive novel therapeutic agent for solid cancer. In this study, we investigated the therapeutic potential of G47Δ for human gastric cancer. In vitro, G47Δ showed good cytopathic effects and replication capabilities in nine human gastric cancer cell lines tested. In vivo, intratumoral inoculations with G47Δ (2 × 105 or 1 × 106 plaque-forming units [PFU]) significantly inhibited the growth of subcutaneous tumors (MKN45, MKN74, and 44As3). To evaluate the efficacy of G47Δ for advanced-stage models of gastric cancer, we generated an orthotopic tumor model and peritoneal dissemination models of human scirrhous gastric cancer (MKN45-luc and 44As3Luc), which have features mimicking intractable scirrhous cancer patients. G47Δ (1 × 106 PFU) was constantly efficacious whether administered intratumorally or intraperitoneally in the clinically relevant models. Notably, G47Δ injected intraperitoneally readily distributed to, and selectively replicated in, disseminated tumors. Furthermore, flow cytometric analyses of tumor-infiltrating cells in subcutaneous tumors revealed that intratumoral G47Δ injections markedly decreased M2 macrophages while increasing M1 macrophages and natural killer (NK) cells. These findings indicate the usefulness of G47Δ for treating human gastric cancer, including scirrhous gastric cancer and the ones in advanced stages.

Anomalies of the right vertebral vein increasing the difficulty of lymph-node dissection along the right recurrent laryngeal nerve: a single-institution, retrospective study.

BACKGROUND: Radical lymph-node dissection along the recurrent laryngeal nerves (RLN) improves the prognosis of patients with esophageal cancer. The RLN is a landmark for achieving adequate lymph-node dissection. However, the right RLN is sometimes covered by the right vertebral veins (VVs), making it undetectable. We investigated the relationship between this anomaly of the right VVs and the challenges of performing lymphadenectomy along the right RLN. METHODS: Patients with esophageal cancer, who underwent thoracoscopic esophagectomy with radical lymph-node dissection, were registered. The patterns of the right VVs were evaluated by preoperative computed tomography. The time required for identifying the right RLN or completing the lymphadenectomy was determined by reviewing surgical videos. RESULTS: In total, 178 patients were enrolled. Eighty patients (45%) had right VVs passing dorsal to the right subclavian artery (Dorsal group). More time was required to detect the right RLN in these cases (11 vs 9.5 min for the other cases, p = 0.034). In the Dorsal group, there were 15 patients who had specific VV patterns: The right VV converged on the lower portion of the right brachiocephalic vein (BCV), or passed through to the more medial side of the mediastinum. These patients required more time for detecting the right RLN (25 vs 9 min, p < 0.0001) and for completing the lymphadenectomy (41 vs 32 min, p = 0.048) than the other cases. CONCLUSION: The right VVs behind the subclavian artery, joining the lower part of the BCV or passing through the medial side, made it difficult to identify the right RLN and complete the lymphadenectomy.